Dataset Information

Thin myelin sheaths as the hallmark of remyelination persist over time and preserve axon function.

ABSTRACT: The presence of thin myelin sheaths in the adult CNS is recognized as a marker of remyelination, although the reason there is not a recovery from demyelination to normal myelin sheath thickness remains unknown. Remyelination is the default pathway after myelin loss in all mammalian species, in both naturally occurring and experimental disease. However, there remains uncertainty about whether these thin sheaths thicken with time and whether they remain viable for extended periods. We provide two lines of evidence here that thin myelin sheaths may persist indefinitely in long-lived animal models. In the first, we have followed thin myelin sheaths in a model of delayed myelination during a period of 13 years that we propose results in the same myelin sheath deficiencies as seen in remyelination; that is, thin myelin sheaths and short internodes. We show that the myelin sheaths remain thin and stable on many axons throughout this period with no detrimental effects on axons. In a second model system, in which there is widespread demyelination of the spinal cord and optic nerves, we also show that thinly remyelinated axons with short internodes persist for over the course of 2 y. These studies confirm the persistence and longevity of thin myelin sheaths and the importance of remyelination to the long-term health and function of the CNS.

SUBMITTER: Duncan ID

PROVIDER: S-EPMC5692595 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Thin myelin sheaths as the hallmark of remyelination persist over time and preserve axon function.

Duncan Ian D ID Marik Rachel L RL Broman Aimee T AT Heidari Moones M

Proceedings of the National Academy of Sciences of the United States of America 20171024 45

The presence of thin myelin sheaths in the adult CNS is recognized as a marker of remyelination, although the reason there is not a recovery from demyelination to normal myelin sheath thickness remains unknown. Remyelination is the default pathway after myelin loss in all mammalian species, in both naturally occurring and experimental disease. However, there remains uncertainty about whether these thin sheaths thicken with time and whether they remain viable for extended periods. We provide two ...[more]

PMID: 29078396

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Project description:Although the mammalian target of rapamycin (mTOR) is an essential regulator of developmental oligodendrocyte differentiation and myelination, oligodendrocyte-specific deletion of tuberous sclerosis complex (TSC), a major upstream inhibitor of mTOR, surprisingly also leads to hypomyelination during CNS development. However, the function of TSC has not been studied in the context of remyelination. Here, we used the inducible Cre-lox system to study the function of TSC in the remyelination of a focal, lysolecithin-demyelinated lesion in adult male mice. Using two different mouse models in which Tsc1 is deleted by Cre expression in oligodendrocyte progenitor cells (OPCs) or in premyelinating oligodendrocytes, we reveal that deletion of Tsc1 affects oligodendroglia differently depending on the stage of the oligodendrocyte lineage. Tsc1 deletion from NG2+ OPCs accelerated remyelination. Conversely, Tsc1 deletion from proteolipid protein (PLP)-positive oligodendrocytes slowed remyelination. Contrary to developmental myelination, there were no changes in OPC or oligodendrocyte numbers in either model. Our findings reveal a complex role for TSC in oligodendrocytes during remyelination in which the timing of Tsc1 deletion is a critical determinant of its effect on remyelination. Moreover, our findings suggest that TSC has different functions in developmental myelination and remyelination.SIGNIFICANCE STATEMENT Myelin loss in demyelinating disorders such as multiple sclerosis results in disability due to loss of axon conductance and axon damage. Encouragingly, the nervous system is capable of spontaneous remyelination, but this regenerative process often fails. Many chronically demyelinated lesions have oligodendrocyte progenitor cells (OPCs) within their borders. It is thus of great interest to elucidate mechanisms by which we might enhance endogenous remyelination. Here, we provide evidence that deletion of Tsc1 from OPCs, but not differentiating oligodendrocytes, is beneficial to remyelination. This finding contrasts with the loss of oligodendroglia and hypomyelination seen with Tsc1 or Tsc2 deletion in the oligodendrocyte lineage during CNS development and points to important differences in the regulation of developmental myelination and remyelination.

Project description:PRéCIS:: There are errors in automated segmentation of the retinal nerve fiber layer (RNFL) in glaucoma suspects or patients with mild glaucoma that appear to persist over time; however, automated segmentation has greater repeatability than manual segmentation.PurposeTo identify whether optical coherence tomography (OCT) segmentation errors in RNFL thickness measurements persist longitudinally.MethodsThis was a cohort study. We used spectral domain OCT (Spectralis) to measure RNFL thickness in a 6-degree peripapillary circle, and exported the native "automated segmentation only" results. In addition, we exported RNFL thickness results after "manual refinement" to correct errors in the automated segmentation, and used the differences in these measurements as "error" in segmentation. We used Bland-Altman plots and linear regression to determine the magnitude, location, and repeatability of RNFL thickness error in all twelve 30-degree sectors and compared the error at baseline to follow-up time points at 6 months, 2 years, 3 years, and 4 years.ResultsWe included 406 eyes from 213 participants. The 95% confidence interval for errors at baseline was -6.5 to +13.2 μm. The correlation between the baseline error and the errors in the follow-up time periods were high (r>0.5, P<0.001 for all). Automated segmentation had a smaller SD of residuals from the longitudinal trend line when compared to manual refinement (1.56 vs. 1.80 μm, P<0.001), and a higher ability (P=0.009) to monitor progression using an analysis of a longitudinal signal-to-noise ratio.ConclusionsErrors in automated segmentation remain relatively stable, and baseline error is highly likely to persist in the same direction and magnitude in subsequent time periods. However, automated segmentation (without manual refinement) is more repeatable and may be more sensitive to glaucomatous progression. Future segmentation algorithms could exploit these findings to improve automated segmentation in the future.

Dataset Information

Thin myelin sheaths as the hallmark of remyelination persist over time and preserve axon function.

Publications

Thin myelin sheaths as the hallmark of remyelination persist over time and preserve axon function.

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